Although almost all mycobacterial species are saprophytic environmental organisms, a few, such as Mycobacterium tuberculosis, have evolved to cause transmissible human infection. By analyzing the recent emergence and spread of the environmental organism M. abscessus through the global cystic fibrosis population, we have defined key, generalizable steps involved in the pathogenic evolution of mycobacteria. We show that epigenetic modifiers, acquired through horizontal gene transfer, cause saltational increases in the pathogenic potential of specific environmental clones. Allopatric parallel evolution during chronic lung infection then promotes rapid increases in virulence through mutations in a discrete gene network; these mutations enhance growth within macrophages but impair fomite survival. As a consequence, we observe constrained pathogenic evolution while person-to-person transmission remains indirect, but postulate accelerated pathogenic adaptation once direct transmission is possible, as observed for M. tuberculosis. Our findings indicate how key interventions, such as early treatment and cross-infection control, might restrict the spread of existing mycobacterial pathogens and prevent new, emergent ones.

尽管几乎所有分枝杆菌物种都是腐生性环境生物，但有少数物种，例如结核分枝杆菌，已经进化到可引起人类传染性感染。通过分析最近环境生物M. abscessus 的出现和传播通过全球囊性纤维化群体，我们已经定义了分枝杆菌病原进化所涉及的关键的、可概括的步骤。我们表明，通过水平基因转移获得的表观遗传修饰物会导致特定环境克隆的致病潜力急剧增加。慢性肺部感染期间的异源平行进化然后通过离散基因网络中的突变促进毒力的快速增加；这些突变会促进巨噬细胞内的生长，但会损害污染物的存活。因此，我们观察到病原进化受到限制，而人与人之间的传播仍然是间接的，但假设一旦可能直接传播，就会加速病原适应，正如对结核分枝杆菌所观察到的那样. 我们的研究结果表明，早期治疗和交叉感染控制等关键干预措施可能如何限制现有分枝杆菌病原体的传播并预防新的、紧急的病原体。